title: The unique N-terminal region of SRMS regulates enzymatic activity and phosphorylation of its novel substrate docking protein 1.
abstract: SRMS (Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) belongs to a family of nonreceptor tyrosine kinases, which also includes breast tumour kinase and Fyn-related kinase. SRMS, similar to breast tumour kinase and Fyn-related kinase, harbours a Src homology 3 and Src homology 2, as well as a protein kinase domain. However, unlike breast tumour kinase and Fyn-related kinase, SRMS lacks a C-terminal regulatory tail but distinctively possesses an extended N-terminal region. Both breast tumour kinase and Fyn-related kinase play opposing roles in cell proliferation and signalling. SRMS, however, is an understudied member of this family. Although cloned in 1994, information on the biochemical, cellular and physiological roles of SRMS remains unreported. The present study is the first to explore the expression pattern of SRMS in breast cancers, its enzymatic activity and autoregulatory elements, and the characterization of docking protein 1 as its first bonafide substrate. We found that, similar to breast tumour kinase, SRMS is highly expressed in most breast cancers compared to normal mammary cell lines and tissues. We generated a series of SRMS point and deletion mutants and assessed enzymatic activity, subcellular localization and substrate recognition. We report for the first time that ectopically-expressed SRMS is constitutively active and that its N-terminal region regulates the enzymatic activity of the protein. Finally, we present evidence indicating that docking protein 1 is a direct substrate of SRMS. Our data demonstrate that, unlike members of the Src family, the enzymatic activity of SRMS is regulated by the intramolecular interactions involving the N-terminus of the enzyme and that docking protein 1 is a bona fide substrate of SRMS.
authors.affiliation: Department of Biochemistry, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Raghuveera K
authors.initials: RK
authors.lastname: Goel
authors.forename: Sayem
authors.initials: S
authors.lastname: Miah
authors.forename: Kristin
authors.initials: K
authors.lastname: Black
authors.forename: Natasha
authors.initials: N
authors.lastname: Kalra
authors.forename: Chenlu
authors.initials: C
authors.lastname: Dai
authors.forename: Kiven E
authors.initials: KE
authors.lastname: Lukong
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D060787:Neoplasm Grading; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; C089510:SRMS protein, human; D019061:src-Family Kinases
keywords: BRK; Dok1; FRK; SRMS; breast cancer